rs121918527

chrX-53535474-G-AchrX-53535474-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3_Moderate PP5

The NM_031407.7(HUWE1):c.12559C>T(p.Arg4187Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 111,071 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4187H) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 22)
• Consequence: HUWE1 NM_031407.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 6.85

Genes affected

HUWE1 (HGNC:30892): (HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1) This gene encodes a protein containing a C-terminal HECT (E6AP type E3 ubiquitin protein ligase) domain that functions as an E3 ubiquitin ligase. The encoded protein is required for the ubiquitination and subsequent degradation of the anti-apoptotic protein Mcl1 (myeloid cell leukemia sequence 1 (BCL2-related)). This protein also ubiquitinates the p53 tumor suppressor, core histones, and DNA polymerase beta. Mutations in this gene are associated with Turner type X-linked syndromic cognitive disability. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-53535473-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 450981.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, HUWE1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882
• PP5: Variant X-53535474-G-A is Pathogenic according to our data. Variant chrX-53535474-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 10678.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=3}. Variant chrX-53535474-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HUWE1	NM_031407.7	c.12559C>T	p.Arg4187Cys	missense_variant	81/84	ENST00000262854.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HUWE1	ENST00000262854.11	c.12559C>T	p.Arg4187Cys	missense_variant	81/84	1	NM_031407.7	P2

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 111071 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33303

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000967

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 111071 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33303

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000967

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, X-linked syndromic, Turner type Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2008	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 14, 2023	Criteria applied: PS4_MOD,PM5,PS3_SUP,PM2_SUP,PP1,PP2 -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Lab, CHRU Brest	-	- -

not provided Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2023	Identified in multiple male family members with intellectual disability in published literature (Froyen et al., 2008); Published functional studies demonstrate a damaging effect on protein function (Opperman et al., 2017: Hunkeler et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19377476, 23871722, 29180823, 29307790, 27130160, 29118367, 18252223, 33948573, 32336296, 34314700, 28445732, 36111624, 37167062) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 15, 2021	This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this variant affects HUWE1 protein function (PMID: 29118367). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HUWE1 protein function. ClinVar contains an entry for this variant (Variation ID: 10678). This variant is also known as c.12229C>T (p.R4077C). This variant has been observed in individual(s) with intellectual disability (PMID: 18252223, 19377476). This sequence change replaces arginine with cysteine at codon 4187 of the HUWE1 protein (p.Arg4187Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. -

Non-syndromic X-linked intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 25, 2020

A hemizygous missense variant was identified, NM_031407.6(HUWE1):c.12559C>T in exon 81 of 84 of the HUWE1 gene. This substitution is predicted to create a major amino acid change from an arginine to a cysteine at position 4187 of the protein, NP_113584.3(HUWE1):p.(Arg4187Cys). The arginine at this position has very high conservation (100 vertebrates, UCSC), and is located within the HECT domain. In silico software predicts this variant to be damaging (Polyphen, SIFT, CADD, Mutation Taster) and the variant is not present in the gnomAD population database. It has been previously reported in patients with X-linked intellectual disability (ClinVar; Hu, H. et al. (2016)). It has also been shown to segregate with disease in one family (Froyen, G. et al. (2008)). In addition, functional studies showed decreased DNA repair capacity and hypersensitivity to oxidative stress in patient lymphoblastoid cells (Bosshard, M. et al. (2017)). A different variant in the same codon resulting in a change to a histidine has been reported as likely pathogenic (ClinVar; Niranjan, T. et al . (2015)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	26
Dann	Benign	0.96
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;.;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.38	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.91	D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.65
MutPred		0.60		.;Loss of catalytic residue at R4187 (P = 0.0822);Loss of catalytic residue at R4187 (P = 0.0822);
MVP		0.92
MPC		1.8
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121918527; hg19: chrX-53562435; COSMIC: COSV99470874; COSMIC: COSV99470874;